Article useful for administration of pharmacologically-active substances transdermally, orally, or by means of implant

ABSTRACT

Described is an article of manufacture useful for administration of pharmacologically-active substances, transdermally, orally or by means of subdermal implant comprising a solid vinyl plastisol layer for contacting a patient&#39;s tissue, internally or externally, the layer containing from about 20 up to about 70% by weight of a polyvinyl chloride resin or a polyvinyl chloride-polyvinyl acetate copolymer containing a minor proportion of vinyl acetate; from about 20-70% plasticizer composition; from about 0.5 up to 35% of a pharmacologically-active substance such as isosorbide dinitrate, nicotine, clonidine, guanfacine, indomethacin, glyceryl trinitrate and prostaglandin and optionally excipients. Also described is the novel plasticizer-polyvinyl chloride composition of matter comprising 1-dodecylhexahydro-2H-azepin-2-one and polyvinyl chloride resin taken together with a pharmacologically-active substance wherein the 1-dodecylhexahydro-2H-azepin-2-one not only acts as a plasticizer but also acts as a penetration enhancer (through tissue) for the pharmacologically-active substance.

This is a divisional of application Ser. No. 847,635, filed Apr. 3,1986; which, in turn, is a continuation-in-part of application for U.S.Letters Patent, Ser. No. 657,911 filed on Oct. 5, 1984 now abandonedwhich, in turn, is a continuation-in-part of application for U.S.Letters Patent, Ser. No. 413,658 filed on Sept. 1, 1982 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates broadly to articles of manufacture foradministration of pharmacologically-active substances, transdermally,orally and by means of implant (e.g., subdermal implant). The devicesconsist essentially of a vinyl chloride polymer or copolymer of vinylchloride containing a majority of vinyl chloride monomeric units and asmall amount of other vinyl monomeric units, e.g., vinyl acetate, andintimately dispersed therewith at least one of saidpharmacologically-active agents and a plasticizer. Examples ofpharmacologically-active agents are isosorbide dinitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin. Contemplated within the scope of this invention aredevices for the controlled release and transdermal administration ofsuch pharmacologically-active agents as nitroglycerine (e.g., in thetreatment of conditions, e.g., angina pectoris).

2. The Prior Art

Many prior art articles of manufacture have been disclosed forcontrolled release delivery of various drugs including transdermaldelivery of nitroglycerin. In general, however, available commercialdevices and indeed devices published in the prior art are limited withrespect to rate of delivery of pharmacologically-active substance.

Canadian Pat. No. 930,668 discloses a bandage for administering drugscomprised of a backing member, a pressure sensitive adhesive, and atleast one reservoir disposed between the backing member and pressuresensitive adhesive. The reservoir is comprised of a systemically activedrug formulation confined within a wall member, the wall member beingformed from a drug release rate controlling material. The reservoir canbe in the form of discrete microcapsules or distinct reservoircompartments or layers. The reservoir can also be in the form of walledcontainers having one or more interior drug-containing chambers, as wellas solid matrixes having a systemically active drug distributedtherethrough. The Canadian patent discloses a wide variety of materialswhich can be used to form the reservoir. Among the materials mentionedare silicone rubbers, hydrophilic polymers of monoesters of an olefinicacid, polyvinylalcohol, polyvinylacetate, plasticized polyvinylchloride,plasticized nylon, collagen, modified collagen, gelatin, and waxes suchas polyethylene wax, oxidized polyethylene wax, hydrogenated castor oiland the like, with the silicone rubbers being preferred. The Canadianpatent does not contain any examples showing the use of plasticizedpolyvinyl chloride, and does not show the use of a PVC plastisol.

Similarly, Zaffaroni, U.S. Pat. No. 3,921,636 issued on Nov. 25, 1975discloses a drug delivery device for administering a drug at acontrolled rate for a prolonged period of time comprising a plurality ofreservoirs containing drug distributed through a matrix. The reservoirsand the matrix are formed of materials permeable to passage of the drug.The rate of drug permeation from the reservoir is lower than the rate ofpermeation through the matrix so that release from the reservoir is thedrug release rate controlling step. Thus, Example 6, at column 15, lines5-30 of U.S. Pat. No. 3,921,636 relates to a polyvinyl chloride resincontaining plasticizer and prednisolone disodium phosphate thusly:

"A drug delivery device for the controlled, oral administration ofwater-soluble prednisolone is prepared as follows: first, a plurality ofdrug reservoirs comprising porous, discrete particles of polymerizedpoly(vinyl chloride) of about 100 microns diameter are prepared bymixing 100 g of suspension grade poly(vinyl chloride) resin with 50 g ofoctyl diphenyl phosphate and 10 g of prednisolone disodium phosphate atroom temperature into a sticky, wet mass. Next, the temperature of themixture is raised to 80° C. for about 3 to 7 minutes, while stirring, toform dry, free flowing, discrete drug reservoirs. The reservoirs areuniformly dispersed through a matrix by mixing 50 g of reservoirscontaining the prednisolone with 140 g of polydimethylsiloxane, 10 g ofsilicone oil, and 0.5 g of stannous octoate. After mixing theingredients, the mixture is charged into pill molds and allowed to curefor 30 minutes. Oral administration of the resulting device yields acontrolled essentially constant rate of release of prednisolonephosphate to the gastrointenstinal tract to give a more uniform bloodlevel of prenisolone over a longer period of time than is achieved whenprednisolone alcohol is administered by standard prior art pills."

Furthermore, as is well known, polyvinyl chloride (PVC) is never usedalone, but is always mixed with other ingredients before beingprocessed. Polyvinyl chloride appeared initially to be an unpromisingresin because of its thermal instability and high rigidity. PVC,however, was then discovered to form a rubber-like material whendissolved hot in high boiling solvents known as plasticizers and cooledto room temperature. PVC is now available in a number of differentphysical forms and types, and its manufacture depends on the formdesired. Thus, PVC is available as a vinyl latex, a dispersion resin, ora general purpose resin. PVC latexes are true colloidal dispersions ofsubmicrometer particles in water, stabilized by a surfactant system, andneed plasticizers in order to form a continuous film. The PVC in vinyllatex is manufactured by emulsion polymerization.

Dispersion resins are produced by emulsion polymerization and are mixedwith plasticizers to form a colloidal dispersion. Such dispersions areknown as plastisols and are easily handled and readily pourable. Whenheated to a temperature of about 148° to 177° C., the plastisol istransformed to a homogeneous melt which, upon cooling to below 50° C.,results in a tough flexible product. The PVC resins made by emulsionpolymerization are hard spheres of particle size between about 0.05 and20 microns, such as between 1 and 20 microns. They do not have theability to absorb plasticizers. Therefore, a mixture containing, forexample, 30% plasticizer and 70 PVC resin, produces a flowable liquid,known as plastisol.

General purpose PVC resins are made by mass and suspensionpolymerization process, and comprise the largest amount of PVC resinsproduced, such as at least 80% of all PVC resins, and are used chieflyto make so-called 100% vinyl products by a variety of molding andextrusion techniques. Resins intended for flexible applications shouldhave good uptake of plasticizer in a dry blending operation and containmore than 25% of a plasticizer system. PVC compounds that contain lessthan 25% plasticizers are referred to as semirigid compounds. The PVCresins manufactured by suspension and bulk polymerization are 50 to 200,such as 100 to 150 microns in diameter, and are like sponges. They arecapable of absorbing large amounts of plasticizers, so that even a 50%plasticizer, 50% PVC resin composition would result in a non-flowing,solid material.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an article ofmanufacture which offers enhanced delivery capability ofpharmacologically-active agents over prior commercial devices(transdermal devices, articles used to orally administerpharmacologically-active agents and subdermal implants used toadminister subdermally pharmacologically-active agents) by providing anarticle capable of efficaciously administering pharmacologically-activeagents such as isosorbide dinitrate, nicotine, indomethacin, clonidine,glyceryl trinitate, guanfacine, and prostaglandin directly from aplastisol resin layer in which the pharmacologically-active agent isincorporated in relatively high concentrations, e.g., from 0.5 up to35%.

This invention also enables the administration of apharmacologically-active agent, such as isosorbide dinitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine, andprostaglandin to be achieved through an article of manufacture, e.g., atransdermal delivery device requiring contact with a relatively smallerarea of a patient's tissue, such as the epidermis in the case of atransdermal delivery device.

Thus, this invention is directed to an article of manufactureincorporating a polyvinyl chloride resin plastisol monolayer foradministration of pharmacologically-active agents transdermally, orallyor by means of subdermal implant to a patient requiring treatment for acondition such as, for example, angina pectoris (in the case of the useof such materials as nitroglycerin). In particular, it has been foundthat pharmacologically-active agents such as isosorbide dinitrate,nicotine, indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin can be homogeneously dispersed in high concentrations in aplastisol of an emulsion polymerized polyvinyl chloride resin andplasticizer; the composition is fused into a solid layer and the layeris applied onto the tissue of a patient (either transdermally, orally orsubdermally) whereby the pharmacologically-active agent is absorbedeither (i) through the patient's skin or (ii) through the patient'sinternal membranes or (iii) directly into the circulation system.

A preferred embodiment comprises a multilayer adhesive bandage deviceincorporating a plastisol monolayer containing homogeneously dispersedpharmacologically-active agents, e.g., isosorbide dinitrate, nicotine,indomethacin, clonidine, glyceryl trinitrate, guanfacine andprostaglandin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a preferred pharmacologically-activeagent delivery device in accordance with this invention.

FIG. 2 is a plan view of a strip of material in accordance with thisinvention viewed from the surface which is applied to the patient'sskin.

FIG. 3 is a plan view of material in accordance with this inventionviewed from the surface away from the surface which is applied to thepatient's skin.

FIG. 4 is an enlarged sectional schematic view of a specific embodimentof the invention; a transdermal device for controlled release of apharmacologically-active agent from a plastisol monolayer through amembrane transdermally.

FIG. 5 is an enlarged sectional schematic view of another embodiment ofthe invention where there is no membrane separating the plastisolmonolayer from the epidermis and whereby pharmacologically-active agentis transported from the plastisol transdermally into the patient.

FIG. 6 is a perspective view of a roll of material in accordance withthis invention.

FIG. 7 is a graph of tensile strenght (PSI) versus percent resincontaining either of isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate or guanfacine, specifically as describedherein in the description of Examples VIII-XIII, infra.

FIG. 8 is graph showing release rate of pharmacologically-active agent(in micrograms per square centimeter per hour) versus percent resin,individually, for isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate or guanfacine specifically inrelationship to Examples XIV-XIX, infra.

FIG. 9 is a graph of plasma concentration (picograms per milliliter)versus time detected in a human subject during the clinical studyconcerning the composition of matter consisting of polyvinyl chlorideresin, dioctyl adipate plasticizer and prostaglandin as specifically setforth in Example XX, infra.

FIG. 10 is a graph showing the effective decrease in diastolic bloodpressure of the human subject observed during the period of patchapplication as specifically set forth in Example XX.

FIG. 11 is a graph of delivery of nitroglycerine versus time resultingfrom the use of the formulation of Example XXI.

FIG. 12 is the infrared spectrum of ADMEX® 760 as used in ExamplesII-XIX.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein with respect to preferred embodimentsincluding transdermal devices containing variouspharmacologically-active agents including, but not limited to,indomethacin having the structure: ##STR1## guanfacine having thestructure: ##STR2## clonidine having the structure: ##STR3## nicotinehaving the structure: ##STR4## isosorbide dinitrate having thestructure: ##STR5## glyceryl trinitrate and prostaglandin (e.g., methyl(±)-[11α,5z (and 5E), 13E, 16R (and 16S)]-16-ethenyl-11,16dihydroxy-9-oxoprosta-5,13-dien-1-oate. It will be understood that otherembodiments may be employed within the spirit and scope of thisinvention.

The articles of our invention are useful for transdermal, oral andsubdermal administration of pharmacologically-active substances andcomprise a solid vinyl plastisol layer (consisting essentially ofpolyvinyl chloride and a plasticizer) for contacting a patient's skin orother membrane. The vinyl plastisol layer contains from about 20 up toabout 70% by weight of a polyvinyl chloride resin which consistsessentially of a vinyl chloride polymer containing, predominantly orcompletely repeating vinyl chloride monomeric units and in an amount ofless than about 10% other repeating vinyl units, e.g., repeating vinylacetate units; from about 20% up to about 70% by weight of thecomposition of one or more plasticizers; from about 0.5 up to about 35%by weight of the total composition of a pharmacologically-activesubstance, such as isosorbide dinitrate, nicotine, indomethacin,clonidine, glyceryl trinitrate, guanfacine or prostaglandin andoptionally other excipients, such as materials which will acceleratetransdermal penetration as exemplified hereinafter.

It has now been found that the release rate of an active agent, which isuniformly dispersed in the vinyl plastisol layer, is criticallydependent upon the proportion of the PVC resin in the composition; andthe release follows a bell shaped curve (FIG. 8), the maximum occurringin the range of 30 to 50% PVC content. This is an unexpected finding,which has not hitherto been known. Such a release behavior permitstailoring of release rates of an agent from the matrix.

The reservoir layers of this invention are relatively weak and less than1500 psi, (FIG. 7), highly flexible and soft materials. In contrast, theflexible vinyl films of commerce are considerably stronger materialsexhibiting tensile strengths of the order of 1,500 to 5,000 psi. Thepolyvinyl chloride resin content of the commercially useful andavailable flexible vinyl films ranges from 50 to 75%. Such materials donot have adequate drug permeating characteristics to serve as suitabledrug delivery reservoirs.

Referring to FIG. 1, the device 1 includes a solid plastisol monolayer 2which is composed of or comprises resin, plasticizer and apharmacologically-active agent as set forth supra.

A formulation for layer 2 may comprise from about 2 up to about 70% byweight of the vinyl resin, from about 20 up to about 70% by weight ofplasticizer composition, from about 0.5 up to about 35% by weight ofpharmacologically-active agent and the remainder being other excipients,such as materials which will enhance skin penetration. We have foundthat the substance 1-dodecylhexahydro-2H-azepin-2-one (also known asAZONE® having the structure: ##STR6## acts as both a plasticizer and asan agent which enhances transdermal penetration ofpharmacologically-active agents such as isosorbide dinitrate,indomethacin and the like as set forth supra. By the same token,N,N-diethyltoluamide having the structure: ##STR7## acts in the samemanner as AZONE®.

Thus, for example, for a device suitable in the treatment of anginapectoris, a specific formulation for layer 2 comprises about 54%polyvinyl chloride (PVC) resin, about 36% dioctyl phthalate (DOP)plasticizer and 10% nitroglycerin. To prepare layer 2, the PVC and DOPare first blended. Due to the explosive character of the drug,dispersion of the nitroglycerin into the resulting PVC/plasticizerplastisol is then carried out under controlled conditions.

The articles of the present invention including the transdermal devicesas well as subdermal implants and orally ingested articles of thepresent invention comprise a polyvinyl chloride plastisol layer in afused state and a pharmacologically-active agent uniformly dispersed inthe fused layer which may be referred to as a reservoir for thepharmacologically-active agent. The polyvinyl chloride reservoir in thepresent invention is prepared from polyvinyl chloride resin and aprimary plasticizer for the resin.

The polyvinyl chloride resin employed in the practice of the presentinvention is that which is specifically used in preparing PVCplastisols, namely, PVC resins which are made by the well known emulsionpolymerization process, which are hard spheres of particle size between0.05 and 20 microns, such as between 1 and 20 microns, for example,between 1 and 5 microns, or between 0.05 and 1 micron, and which do nothave the ability to absorb plasticizers to any great extent. Instead,the plasticizer wets the resin particles at room temperature and onlythen very slowly penetrates and solvates the resin. These PVC resinswhen mixed with plasticizers, such as a mixture of 30% primaryplasticizer, 70% PVC resin, give a flowable liquid known as plastisolwhich can then be fused at, for example, approximately 250° F. forapproximately 30 seconds to provide a solid polymer layer. The PVC resinemployed in the present invention is in contrast to the general purposePVC resins which are produced by suspension or bulk polymerization andwhich are used in calendering and extrusion processes, which are 50 to200 microns, such as 100 to 150 microns in diameter, and are likesponges. Thus, the general purpose resins are capable of absorbing largeamounts of plasticizers so that even a 50% DOP and 50% PVC resin wouldresult in a non-flowing solid material. The molecular weight of the PVCresins employed in the present invention preferably is a weight averagemolecular weight between 80,000 and 250,000, such as a weight averagemolecular weight of 123,000. A suitable polyvinyl chloride resin is onesold by Occidental Chemical Co. under the designation FPC 6338containing about 96% vinyl chloride monomer units of about 4% vinylacetate monomer units. Thus, the polyvinyl chloride resin can becopolymer containing preferably at least 90% by weight vinyl chloridemonomer units, such as a copolymer based on vinyl chloride and vinylacetate.

The polyvinyl chloride resin generally is present in the layer in anamount of 10 to 75 weight percent, preferably 20 to 70 weight percent,based on the total weight of the vinyl plastisol composition.

The primary plasticizer which is employed in the present invention canbe dioctylphthalate (DOP), benzylbutylphthalate,tri-2-ethylhexylmalaete, dioctyl adipate, epoxidized soybean oil,polymeric adipate plasticizers, which are polymers of adipic acid with amonomer, such as propylene glycol, and for example can be obtained underthe designation Drapex 334F from Witco Chemical Corp., or any otherknown primary plasticizer for PVC which is biologically acceptable.

The other examples of polyester adipates, glutarates and sebacates are:

polyester adipate (P)P-644;

polyester glutarate (P)P-530;

polyester glutarate (P)P540;

polyester glutarate (P)P-550;

polyester glutarate (P)P-7035;

polyester glutarate (P)P-7035M;

polyester glutarate (P)P-7046;

polyester glutarate (P)P-7092; and

polyester sebacate (P)P-1070

manufactured by the C. P. Hall Co., 7300 S. Central Avenue, Chicago,Ill. 60638. Other preferred plasticizers are those which are known as"phthalate" plasticizers, for example, ADMEX® 760 which is a highmolecular weight (MW=8000) phthalate plasticizer manufactured by theSherex Division of Nuodex Inc. In general, polyester plasticizers whichare polyesters of (i) 1,4-terephthalic acid and/or 1,2-phthalic acidwith (ii) ethylene glycol or 1,3-propylene glycol having molecularweights in the range of 4000-10,000 are preferred.

Another preferred plasticizer which also acts as a skin penetratingenhancer for pharmacologically-active drugs which are intended fortransdermal delivery from devices such as those set forth in FIGS. 1, 5and 6 is the compound having the structure: ##STR8## known as AZONE®marketed by the Nelson Research and Development Co. The compositioncomprising PVC and the compound having the structure: ##STR9## is anovel composition of matter.

Mixtures of known plasticizers can be used. The term "primaryplasticizers" as used herein refers to a plasticizer which can be usedalone to effect plasticization and is highly compatible with PVC at highconcentrations, such as, for example, 150 parts per hundred. Primaryplasticizers are contrasted with "secondary plasticizers" which, becauseof limited compatibility with PVC, cannot be used alone. See,Kirk-Othmer Encyclopedia of Chemical Technology, Volume 23, 3rd Edition,especially pages 913 and 914 for a discussion of primary and secondaryplasticizers, which is incorporated by reference herein.

The primary plasticizer generally is present in an amount of 20 to 85weight percent, preferably 20 to 70% based on the total weight of thevinyl plastisol layer.

The PVC plastisol may optionally contain other additives or "excipients"useful in the practice of this invention, for example, material whichenhance skin penetrated of the pharmacologically-active substances(e.g., 1,6-hexanediol and n-decyloleate) and thickeners, e.g., silica(preferably "fumed" silica, for example, AEROSIL® in an amount of from1-6% of the layer).

With reference to FIG. 1, the blended plastisol containing, for example,PVC, DOP and nitroglycerin is then coated at a rate of about 36ounces/yd² on a backing, and then fused into solid plastisol layer 2.The backing may be a single layer of drug impermeable plastic or othermaterial, but is preferably composed of two layers 3 and 4. Layer 3 maybe MYLAR® (polyester produced from ethylene glycol and phthalicanhydride) about 0.5 mils thick, and layer 4 may be PVC, about 4 milsthick. The backing 3, 4 substantially blocks loss of drug from theplastisol layer 2 other than in the direction of the surface which, inuse, will contact the patient's skin.

The blended plastisol which is coated on the backing can be fused into ahomogeneous solid by heating it for a short period, such as 15 to 30seconds, at a temperature of, for example, 250° to 280° F. The use of aplastisol to form solid layer 2 enables layer 2 to be formed by using alow temperature for a short period of time, and provides conditionswhich do not affect the stability of the pharmacologically-activeagents.

A strip of solid plastisol layer 2 and backing 3,4 is then bonded to apressure-sensitive adhesive layer 5 which in turn is provided with anon-adhesive backing 6 such as one made of plastic, moisture-prooffabric, aluminum foil, etc.

When not in use, the entire surface intended for skin contact ispreferably covered with a release paper 7 or the like which is removedto expose surfaces of the adhesive layer 5 and drug containing plastisollayer 2 for application to the patient's skin.

FIG. 2 shows a plan view of a strip of material 20 during the stage ofmanufacture at which a strip of the plastisol 2 (backing 3,4 not shown)has been applied to the adhesive tape (backing 6 not shown). For thepreferred device for the controlled administration ofpharmacologically-active agent, e.g., indomethacin, isosorbidedinitrate, nicotine, clonidine, glyceryl trinitrate, guanfacine orprostaglandin, a plastisol strip preferably about one inch (1") in widthis applied on a two and one-half inch (21/2") wide pressure-sensitiveadhesive strip.

FIG. 3 shows a plan view of a strip of the material 30 in accordancewith this invention; spaced lines 31 may be embossed or printed on thesurface away from skin contact so that the patient may convenientlymeasure out and cut off the proper amount of tape device to provide theprescribed daily dosage. For a device for administering thepharmacologically-active agent, e.g., nitroglycerin, for example, asegment 1" long cut from the longer tape (resulting in an approximatelyone square inch (1 sq. in.) of active surface against the patient'sskin) will provide a dosage of about 17 mg/24 hours; this is believed tobe an enhanced rate of delivery compared with commercially availabletransdermal drug delivery devices and also will provide the patient witha bandage device having a surface area much smaller than found inpreviously available devices.

Referring to FIG. 4, the components of embodiment 33 are backing layer34, a reservoir layer 35 that contains supplies of percutaneousabsorption enhancer and pharmacologically-active substance, such asindomethacin, a diffusion membrane layer 36 and a peripheral ring 37 ofcontact adhesive. The diffusion membrane layer may be composed of apolymer, such as a copolymer of ethylene and methyl acrylate with themethyl acrylate being in the range of 2-90% by weight of the polymer, orblends of such copolymer with low density polyethylene, high densitypolyethylene or linear low density polyethylene. The contact adhesivecomponent of embodiment 33 is in the form of a peripheral ring.Optionally, backing layer 34 may also be a semi-permeable membrane.Neither the pharmacologically-active agent, e.g., isosorbide dinitratenor enhancer passes through ring 37 and it therefore need not bepermeable to those compositions. Optionally, the contact adhesive may beattached directly to the membrane 36, in which case the adhesive isselected so that it is permeable to the active agent. Secondly, thebasil surface from which the pharmacologically-active substance andenhancer (e.g., AZONE® is transferred to the skin is defined bydiffusion membrane layer 36. The backing layer is not flat but insteadforms a pocket or cavity in which the reservoir layer is held. The outeredge of the backing layer is sealed to the peripheral ring of thecontact adhesive as more specifically set forth in U.S. Pat. No.4,379,454 issued on Apr. 12, 1983, the disclosure of which isincorporated herein by reference. Similarly, an article within thecontemplation of our invention need not have a matrix as is illustratedin FIG. 5 wherein the backing 61 totally surrounds thePVC-plastisol-plasticizer matrix 62 and is firmly in placed as with anadhesive on the skin 63.

As shown in FIG. 6, the device of the invention may conveniently beprovided in the form of a tape roll 50 from which daily dosagerequirements may be clipped by the patient.

The device is capable of application to humans or other animals capableof usefully absorbing drugs through the skin.

Other embodiments of our invention are those useful in, for example,U.S. Pat. Nos. 4,573,996 and 4,573,995 issued on Mar. 4, 1986, thespecifications for which are incorporated by reference herein.

EXAMPLE I

A plastisol was formed by mixing 54% of a polyvinyl chloride resin soldunder the designation FPC 6338 by Occidental Chemical Corp. and having aparticle size between 1 and 5 microns, 36% DOP, and 10% nitroglycerin.The product was coated onto 1 mil polyester (MYLAR) film and cured at280° F. The final product consisted of 8.8% nitroglycerin, 31.8% DOP,47.8% FPC 6338, 11.6% polyester. This product can be used for deliveryof nitroglycerin percutaneously.

EXAMPLES II-XIX FUSED PLASTISOL DRUG RESERVOIR EXAMPLES

Fused plastisol drug reservoirs having variable PVC: plasticizer ratioswere prepared by heating cast films of the drug containing plastisols at290° F. for 60 seconds. The drugs used were isosorbide dinitrate (ISDN)and nicotine. AZONE® having the structure: ##STR10## (registeredtrademark of the Nelson Research and Development Co.) and ADMEX® 760(which is a high molecular weight (MW=8000) phthalate plasticizermanufactured by the Sherex Division of Nuodex Inc.) were used as primaryplasticizers in the case of the ISDN and the nicotine reservoirs,respectively. The films, thus prepared, were optically transparent. FIG.12 is the infrared spectrum of ADMEX® 760.

The stress-strain properties of the films were determined employingstandard procedures using Instron Universal Testing Instrument. Theability of the reservoir to release the drug was evaluated by measuringthe dissolution rate of the drug in a fluid medium (receptor phase) whena known surface area of the drug reservoir film was exposed to an excessof the receptor phase at 31° C. The dissolution rate studies wereconducted using a Franz diffusion cell. The receptor phase for thenicotine study was pH 4.0 citric acid buffer solution (an aqueoussolution containing 1.2% citric acid and 1.1% disodium hydrogenphosphate), and that for the ISDN study was an aqueous solutioncontaining 20% polyethylene glycol 400. The dissolution rate of the drugwas calculated from the change in concentration of the drug in thereceptor phase at different time intervals. The nicotine and ISDNconcentrations were determined by ultraviolet spectroscopy and highpressure liquid chromatographic procedures, respectively.

EXAMPLES II-VII

In the following formulations (A-F in each of Examples II-VII), thefollowing terms have the following meanings as now given:

    ______________________________________                                        ISDN:     Isosorbide dinitrate having the structure:                                     ##STR11##                                                          AZONE:    The compound having the structure:                                             ##STR12##                                                          6338:     A vinyl chloride vinyl acetate copolymer                                      having a vinyl acetate content of 4.0-4.5%                                    manufactured by the Occidental Chemical                                       Corporation.                                                        ADMEX:    A high molecular weight (MW = 8000)                                           phthalate plasticizer manufactured by the Sherex                              Division of Nuodex Inc.                                             Nicotine: The compound having the structure:                                             ##STR13##                                                          Indomethacin:                                                                           The compound having the structure:                                             ##STR14##                                                          Clonidine:                                                                              The compound having the structure:                                             ##STR15##                                                          GTN:      Glyceryl trinitrate.                                                Guan:     Guanfacine having the structure:                                               ##STR16##                                                          DOP:      Dioctyl phthalate.                                                  HG:       1,6-Hexylene glycol.                                                Cer 140:  "Ceraphyl 140" being n-decyl oleate.                                ______________________________________                                    

EXAMPLE II

    ______________________________________                                        ISDN FORMULATIONS:                                                            "A"          "B"     "C"       "D"   "E"                                      ______________________________________                                        ISDN   15.0%     15.0%   15.0%   15.0% 15.0%                                  AZONE  59.5%     51.0%   42.5%   34.0% 25.5%                                  6338   25.5%     34.0%   42.5%   51.0% 59.5%                                  ______________________________________                                    

EXAMPLE III

    ______________________________________                                        NICOTINE FORMULATIONS                                                         "A"          "B"     "C"       "D"   "E"                                      ______________________________________                                        Nicotine                                                                             30.0%     30.0%   30.0%   30.0% 30.0%                                  ADMEX  49.0%     42.0%   35.0%   28.0% 21.0%                                  6338   21.0%     28.0%   35.0%   42.0% 49.0%                                  ______________________________________                                    

EXAMPLE VI

    ______________________________________                                        INDOMETHACIN FORMULATIONS                                                            "A"   "B"       "C"     "D"     "E"                                    ______________________________________                                        Indomethacin                                                                           15.0%   15.0%     15.0% 15.0%   15.0%                                AZONE    25.5%   34.0%     42.5% 51.0%   55.0%                                6338     59.5%   51.0%     42.5% 34.0%   30.0%                                ______________________________________                                    

EXAMPLE V

    ______________________________________                                        CLONIDINE FORMULATIONS                                                        "A"          "B"     "C"       "D"   "E"                                      ______________________________________                                        Clonidine                                                                            20.0%     20.0%   20.0%   20.0% 20.0%                                  ADMEX  60.0%     55.0%   50.0%   45.0% 41.0%                                  6338   20.0%     25.0%   30.0%   35.0% 44.0%                                  ______________________________________                                    

EXAMPLE VI

    ______________________________________                                        GTN FORMULATIONS:                                                             "A"          "B"     "C"       "D"   "E"                                      ______________________________________                                        GTN    8.0%      8.0%    8.0%    8.0%  8.0%                                   ADMEX  62.0%     53.0%   46.0%   39.0% 32.0%                                  6338   30.0%     39.0%   46.0%   53.0% 60.0%                                  ______________________________________                                    

EXAMPLE VII

    ______________________________________                                        GUANFACINE FORMULATIONS:                                                      "A"          "B"     "C"       "D"   "E"                                      ______________________________________                                        Guan.  30.0%     30.0%   30.0%   30.0% 30.0%                                  DOP    25.0%     21.0%   18.0%   14.0% 10.0%                                  HG     12.5%     12.5%   12.5%   12.5% 12.5%                                  Cer 140                                                                              12.5%     12.5%   12.5%   12.5% 12.5%                                  6338   20.0%     24.0%   27.0%   31.0% 35.0%                                  ______________________________________                                         NOTE: The hexylene glycol enhances the permeability transdermally of the      guanfacine. The Cer 140 adjusts the activity of the guanfacine in the         reservoir.                                                               

EXAMPLES VIII-XIII

In the following examples, the following terms have meanings as givenherein:

    ______________________________________                                        ISDN:     Isosorbide dinitrate having the structure:                                     ##STR17##                                                          Nicotine: The compound having the structure:                                             ##STR18##                                                          Indomethacin:                                                                           The compound having the structure:                                             ##STR19##                                                          Clonidine:                                                                              The compound having the structure:                                             ##STR20##                                                          GTN:      Glyceryl trinitrate.                                                Guan:     Guanfacine having the structure:                                               ##STR21##                                                          ______________________________________                                    

FIG. 7 shows tensile strength versus percent resin for each of the aboveformulations. The curve indicated by reference numeral 70 is the curvefor clonidine. The curve indicated by reference numeral 71 is the curvefor guanfacine. The curve indicated by reference numeral 72 is the curvefor indocin. The curve indicated by reference numeral 73 is the curvefor nicotine. The curve indicated by reference numeral 74 is the curvefor isosorbide dinitrate. The curve indicated by reference numeral 75 isthe curve for glyceryl trinitrate.

EXAMPLE VIII

    ______________________________________                                        ISDN:                                                                         % Resin      Tensile Strength                                                 ______________________________________                                        25.5          57.21                                                           34.0         144.09                                                           42.5         399.54                                                           51.0         663.81                                                           59.5         1077.53                                                          ______________________________________                                    

EXAMPLE IX

    ______________________________________                                        NICOTINE:                                                                     % Resin      Tensile Strength                                                 ______________________________________                                        21.0          54.22                                                           28.0         125.51                                                           35.0         204.39                                                           42.0         300.57                                                           49.0         671.30                                                           ______________________________________                                    

EXAMPLE X

    ______________________________________                                        INDOMETHACIN:                                                                 % Resin      Tensile Strength                                                 ______________________________________                                        30.0          99.63                                                           34.0         162.00                                                           42.5         495.00                                                           51.0         764.00                                                           59.5         1447.00                                                          ______________________________________                                    

EXAMPLE XI

    ______________________________________                                        CLONIDINE:                                                                    % Resin      Tensile Strength                                                 ______________________________________                                        20.0         118.36                                                           25.0         228.70                                                           30.0         308.99                                                           35.0         487.65                                                           44.0         440.16                                                           ______________________________________                                    

EXAMPLE XII

    ______________________________________                                        GTN:                                                                          % Resin      Tensile Strength                                                 ______________________________________                                        30.0          17.53                                                           39.0          74.90                                                           46.0         116.43                                                           53.0         738.85                                                           60.0         1339.02                                                          ______________________________________                                    

EXAMPLE XIII

    ______________________________________                                        GUAN:                                                                         % Resin      Tensile Strength                                                 ______________________________________                                        20.0          84.83                                                           24.0         128.40                                                           27.0         180.50                                                           31.0         131.50                                                           35.0         203.21                                                           ______________________________________                                    

EXAMPLES XIV-XIX

In the following examples, the following terms have meanings as setforth below:

    ______________________________________                                        ISDN:     Isosorbide dinitrate having the structure:                                     ##STR22##                                                          Nicotine: The compound having the structure:                                             ##STR23##                                                          Indomethacin:                                                                           The compound having the structure:                                             ##STR24##                                                          Clonidine:                                                                              The compound having the structure:                                             ##STR25##                                                          GTN:      Glyceryl trinitrate.                                                Guan:     Guanfacine having the structure:                                               ##STR26##                                                          ______________________________________                                    

EXAMPLE XIV

    ______________________________________                                        ISDN:                                                                                % Resin                                                                              Release                                                         ______________________________________                                               25.5   91.66                                                                  34.0   108.90                                                                 42.5   93.50                                                                  51.0   65.71                                                                  59.5   50.29                                                           ______________________________________                                    

EXAMPLE XV

    ______________________________________                                        NICOTINE:                                                                            % Resin                                                                              Release                                                         ______________________________________                                               21.0   40.76                                                                  28.0   122.78                                                                 35.0   218.25                                                                 42.0   243.55                                                                 49.0   216.18                                                          ______________________________________                                    

EXAMPLE XVI

    ______________________________________                                        INDOMETHACIN:                                                                        % Resin                                                                              Release                                                         ______________________________________                                               30.0   36.14                                                                  34.0   87.01                                                                  42.5   68.75                                                                  51.0   24.49                                                                  59.5   8.65                                                            ______________________________________                                    

EXAMPLE XVII

    ______________________________________                                        CLONDINE                                                                             % Resin                                                                              Release                                                         ______________________________________                                               20.0   103.67                                                                 25.0   108.22                                                                 30.0   80.85                                                                  35.0   82.18                                                                  44.0   62.81                                                           ______________________________________                                    

EXAMPLE XVIII

    ______________________________________                                        GTN:                                                                                 % Resin                                                                              Release                                                         ______________________________________                                               30.0   41.91                                                                  39.0   48.54                                                                  46.0   42.63                                                                  53.0   46.02                                                                  60.0   35.81                                                           ______________________________________                                    

EXAMPLE XIX

    ______________________________________                                        GUAN:                                                                                % Resin                                                                              Release                                                         ______________________________________                                               20.0   31.72                                                                  24.0   56.85                                                                  27.0   63.06                                                                  31.0   88.41                                                                  35.0   165.82                                                          ______________________________________                                    

FIG. 8 is a graph showing release rate in micrograms per squarecentimeter per hour versus percent resin. The curve indicated byreference numeral 80 is the curve for nicotine. The curve indicated byreference numeral 81 is the curve for clonidine. The curve indicated byreference numeral 82 is the curve for guanfacine. The curve indicated byreference numeral 83 is the curve for isosorbide dinitrate. The curveindicated by reference numeral 84 is the curve for indomethacin. Thecurve indicated by reference numeral 85 is the curve for glyceryltrinitrate.

EXAMPLE XX TRANSDERMAL DELIVERY OF PROSTAGLANDIN FROM DRUG RESERVOIRHUMAN CLINICAL STUDY

I. Drug: Prostaglandin (American Cyanamid Co.)

Methyl(±)-[11α, 5z (and 5E), 13E, 16R (and 16S)]ethenyl-11,16dihydroxy-9-oxoprosta-5,13-dien-1-oate (an analog of Prostaglandin E₂).

II. Pharmacological Activity: Antihypertensive

III. Patch Formula:

PVC Resin: 59.7%

Dioctyl Adipate: 38.2%

50% Prostaglandin in Dioctyl Adipate: 2.1%

IV. Results: A. The Drug Concentration up to 500 pg/ml was detected in ahuman subject. (FIG. 9) B. Effective decrease in diastolic bloodpressure of the human subject was observed during the period of patchapplication. (FIG. 10)

The curve indicated by reference numeral 90 shows plasma concentrationin picograms per ml versus time in hours. The curve indicated in FIG. 10by reference numeral 101 shows mean decreases in sitting diastolic bloodpressure following administration of the subject patch formula to normalsubjects in a cross over study (sample size=15). The units of pressureare mmHg and the units of time are in hours.

EXAMPLE XXI TRANSDERMAL DELIVERY OF NITROGLYCERIN FROM DRUGRESERVOIR-HUMAN CLINICAL STUDY

Drug: Nitroglycerin (Glyceryl trinitrate)

Pharmacological Activity: Vasodilator

Patch Formulation:

    ______________________________________                                        Ingredient        Percentage                                                  ______________________________________                                        Nitroglycerin     9.6%                                                        Dioctyl Phthalate 76.8%                                                       PVC Resin         9.6%                                                        Aerosil (Fumed Silica)                                                                          4.0%                                                        ______________________________________                                    

Results:

The patch delivered adequate nitroglycerin through skin of humansubjects to provide a concentration of 0.1 to 0.2 ng/ml in the bloodplasma for a period of 3 days as set forth in FIG. 11. The graphindicated by reference numeral 111 is a graph of delivery of glyceryltrinitrate in nanograms/ml versus time (in hours)

EXAMPLE XXII IN VIVO TRANSDERMAL DELIVERY OR ISOSORBIDE DINITRATE(ISDN)-FROM DRUG RESERVOIR

I. Patch Formula:

ISDN (50% on Latose): 15%

PVC Resin: 30%

AZONE®: 32%

Isopropyl Myristate: 20%

Aerosil (Fumed Silica): 3%

II. Pharmacological Activity: Vasodilator

III. Test Protocol:

Formulations containing 7.5% ISDN, and 0, and 32% AZONE® respectivelywere tested in vivo on monkeys. Each formulation was tested on twomonkeys for six consecutive days. The patches were firmly placed on theshaved upper innerarm each morning and were left in place for eighthours. For each test condition blood samples of approximately 3-4 mlwere withdrawn from an indwelling catheter inserted into the saphenousvein. Blood samples were drawn at 0 (prior to patch application), 4 and8 hours after dosing. The eight-hour samples was drawn before thepatches were removed. The plasma component was immediately separatedfrom the blood by centrifugation at 1200 rpm for 5 minutes, and frozenat -20° C. The samples were then extracted to determine concentrationsof ISDN and its metabolites Isosorbide 5-mononitrate (5-ISMN) andIsosorbide 2-Mononitrate (2-ISMN).

Upon removal of the patches, the side of application was washed withdilute alcohol and inspected visually. Any changes in the condition ofthe skin (such as erythema or edema) was scored according to the DrazeScoring System. This inspection was repeated 30 minutes and again beforenext patch application.

IV. Results:

The mean plasma ISDN and metabolite results for the patches are shown inTable I. An increase of 300% to 400% in plasma ISDN concentration wasobserved for patches containing 32% AZONE®.

A maximum of 43.8% ng/ml of plasma ISDN was obtained from 2 patches witha total surface area of 12.5 cm². However, the data did not suggest thatthere was a linear increase of plasma level with surface area of patch.In general, doubling the patch surface area more than doubled the plasmalevel, for ISDN as well as the metabolites.

                  TABLE I                                                         ______________________________________                                        8 HOURS IN VIVO RESULTS OF ISDN PATCHES                                       ON MONKEYS AVERAGE CONCENTRATION (ng/ml)                                      % AZONE  ®                                                                          No. Patches*                                                                             ISDN     5 ISMN 2 ISMN                                   ______________________________________                                         0        1          3.46     12.75  3.05                                               2          19.39    55.52  12.67                                    12        1          6.08     23.56  4.64                                               2          30.23    68.43  17.11                                    32        1          14.14    42.01  9.75                                               2          43.85    87.85  23.75                                    ______________________________________                                         *Patch size was 6.25 cm.sup.2.                                           

What is claimed is:
 1. A composition of matter comprising a polyvinylchloride resin intimately admixed with a plasticizing quantity of thecompound having the structure: ##STR27##
 2. A composition of mattercomprising a polyvinyl chloride resin intimately admixed withN,N-diethyltoluamide.